RESUMO
Autonomic dysfunction has been described in patients with Huntington's disease, but it is unclear if these changes in autonomic tone are related to the central autonomic network. We performed a pilot study to investigate the relationship between the integrity of the central autonomic network and peripheral manifestiations of autonomic dysfunction in premanifest Huntington's disease. We recruited male participants with pre-motor-manifest Huntington's disease and a comparison group consisting of healthy, male participants of approximately the same age. As this was a pilot study, only males were included to reduce confounding. Participants underwent a resting-state functional magnetic resonance imaging study to quantify functional connectivity within the central autonomic network, as well as a resting 3-lead ECG to measure heart rate variability with a particular focus on the parasympathetic time-domain measures of root mean square of successive differences between normal heartbeats. The pre-motor-manifest Huntington's disease participants had significantly decreased root mean square of successive differences between normal heartbeats values compared with the healthy comparison group. The pre-motor-manifest Huntington's disease group had significantly lower functional connectivity within the central autonomic network, which was positively correlated with root mean square of successive differences between normal heartbeats. Patients with pre-motor-manifest Huntington's disease have reduced functional connectivity within the central autonomic network, which is significantly associated with observed changes in autonomic function.
RESUMO
BACKGROUND: Impaired brain energy metabolism is a key feature of Parkinson's disease (PD). Terazosin (TZ) binds phosphoglycerate kinase 1 and stimulates its activity, which enhances glycolysis and increases ATP levels. Preclinical and epidemiologic data suggest that TZ may be neuroprotective in PD. We aimed to assess target engagement and safety of TZ in people with PD. METHODS: We performed a 12-week pilot study in people with PD. Participants were randomized to receive 5 mg TZ or placebo. Participants and study personnel were blinded. We assessed TZ target engagement by measuring brain ATP with 31P-magnetic resonance spectroscopy (MRS) and whole blood ATP with a luminescence assay. Robust linear regression models compared changes between groups controlling for baseline brain and blood ATP levels, respectively. We also assessed clinical measures of PD and adverse events. RESULTS: Thirteen participants were randomized. Mild dizziness/lightheadedness was more common in the TZ group, and three participants taking TZ dropped out because of dizziness and/or orthostatic hypotension. Compared to the placebo group, the TZ group had a significant increase in the ratio of ßATP to inorganic phosphate in the brain. The TZ group also had a significant increase in blood ATP levels compared to the placebo group (p < 0.01). CONCLUSIONS: This pilot study suggests that TZ may engage its target and change ATP levels in the brain and blood of people with PD. Further studies may be warranted to test the disease-modifying potential of TZ.
